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09

Jul

2014

Stem Cell Decline and Loss of Organ Mass with Aging

There are a few hundred different types of cell in the body, a collection of types for each major organ and variety of tissue. Cell populations turn over at various different rates, with new cells supplied by dedicated supporting stem cells, existing cells in the tissue dividing, and old cells removing themselves from the picture through forms of programmed cell death. The cells that line your gut have a very short life of a few days. Blood cells are usually in circulation for months. Many nervous system cells last your entire life. Unfortunately old cells that have divided many times don't always self-destruct, and instead slide into a form of growth arrest known as senescence. There they stay unless destroyed by the immune system, making life difficult for surrounding cells and degrading tissue function. The growing number of senescent cells in all tissues is one of the causes of degenerative aging.

One of the other problems in this context of tissue maintenance is that the supply of new cells dwindles with age. Stem cells stop doing their jobs and spend more time in dormant states. As a result tissue and organ function begins to falter and eventually fail. The consensus viewpoint in the research community is that this is an evolutionary adaptation that reduces cancer risk. The big important difference between humans and possibly immortal highly regenerative lower animals such as hydra is that we are complex and the continuation of an individual's life depends on maintaining the small-scale accumulated structure of our nervous system - we can't just throw it all out and regenerate it as needed. If you have a brain, or even just a rudimentary central nervous system, that rules out the sort of high-powered always-on stem cell activity that allows a hydra to be (possibly) ageless and renew or regrow any lost part.

One of the manifestations of diminished stem cell activity with aging is that we lose tissue mass in most of the important organs. This may be a straightforward consequence of lack of replenishment, but as the paper linked below notes it starts fairly early in adult life. In this viewpoint, the well-known involution of the thymus at end of childhood is just the most noticeable of a set of similar changes that occur throughout adulthood and into old age. Loss of stem cell activity is something that has to be fixed by any comprehensive rejuvenation toolkit of the near future, or at least it has to be fixed to the extent that it is not just a reaction to forms of tissue damage. It is quite likely that stem cell decline in old age is in fact largely driven by epigenetic changes that in turn arise due to rising levels of - for example - mitochondrial DNA damage, metabolic waste in cells and between cells, accumulated senescent cells, and so forth. If this damage is repaired, then stem cells should return to work.

We employed published data to estimate representative mean values of cell turnover times for 31 different organs and tissues in adult humans and animals (when data in humans were lacking) as well as functional mass loss for 5 organs, accounting for actual mass loss and tissue conversion to fat, in humans over the adult period, age 25 to 70. Actual and functional organ mass was lost from age 25 to 70 years in all organs studied, except the heart and prostate. We found that greater actual and functional mass loss was significantly associated with the log of shorter cell turnover times. We propose that this is characteristic of stem cell exhaustion and replicative senescence.

We found that, in normal ageing, organ mass loss is associated with high cell turnover. At the Hayflick limit, cells go into a senescent state of persistent cell cycle arrest, or undergo cell death, usually by p53-dependent apoptosis. This increase in apoptotic and senescent cells with ageing represents a loss of actual and functional tissue. We suggest that this mass loss may be characteristic of stem cell exhaustion as seen in muscle and marrow and that "replicative senescence" may play a role in this process. Stem cell pools can diminish with age. For example, the number of satellite cells in human skeletal muscle declines from young to old adults. Furthermore, stem cell exhaustion may be due to cell dysfunction characterised by decreased self-renewal and quiescence, increased doubling time, degraded niches and impaired terminal differentiation.

Our analysis of previously published data indicates that mass loss in major organs generally begins between 21 and 35 years of age for reproductive organs and between 22 and 50 years for non-reproductive organs, although involution of the thymus begins even earlier. Likewise, many physiological functions show a decline from 30 years of age. Similarly some aspects of age-related cognitive decline begin in healthy educated adults when they are in their 20s and 30s. Therefore, our evaluation of organ mass loss, especially in terms of functional tissue reduction, is in parallel with, and likely contributes to, the decline in physiological and cognitive function. Furthermore, these studies also provide substantial, but not universal, evidence for the acceleration of actual and functional mass loss in organs. As the few studies dedicated to these ageing changes indicate that these functional tissue losses may be considerable, this suggests that even measures of body cell mass underestimate the true accelerating loss of functional tissue with ageing. Indeed, accelerated functional mass loss could provide an increased elimination of precancerous cells in the very elderly, perhaps providing an explanation, among others, for the decrease in cancer rates observed after age 75.

The general prevalence of the Hayflick limit in human somatic cells, including stem cells, means this aspect of human ageing is likely an evolutionary adaptation, as antidotes against this shortening, such as telomerase, are not employed at sustaining levels in somatic tissues. However, telomere-maintenance mechanisms are fully operational in human germ cells, most neoplasms (clonal cells) and biologically immortal species such as Hydra vulgaris that reproduce asexually when food is plentiful. The immortality (and lack of reported mass loss) of Hydra is assigned to FoxO stem cell maintenance gene variants, which are also found in human stem cells, albeit at levels insufficient to maintain stem cells. Interestingly, a genetic variant in the FOXO3a gene region is more common in German centenarians compared with younger controls.

Our review supports a strongly significant association between cell proliferation and functional mass loss, the latter being an important indicator of fitness and ageing. We found that two-thirds of the human variability of mass loss can be assigned to the log of tissue turnover times. We suggest that this is likely characteristic of replicative senescence of stem cells, which, as the immortal Hydra demonstrates, is not a biological imperative but an evolutionary adaptation, likely suppressing cancer in humans. The onset of functional mass loss first becomes apparent soon after growth terminates, during the early part of the reproductive period, when selective pressure is still considerable. We make the case that, although the deceleration of cell turnover helps mitigate the erosion of maintenance-deficient telomeres, there is an acceleration of functional mass loss in old age as biological conditions change from those existing in early development, when the selective pressure on genetic trade-offs is most influential.

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